CuBr2-promoted intramolecular bromocyclization of N-allylamides and aryl allyl ketone oximes

Article abstract of DOI:10.1016/j.tet.2017.10.025

A new and easy-to-perform route to 2-oxazolines amd isoxazolines was reported. Using CuBr₂ as both the bromide source and the reaction promoter, bromocyclization of N-allylamides and allyl ketone oximes proceeded readily, leading to oxazolines

Full text of DOI:10.1016/j.tet.2017.10.025

Accepted Manuscript
CuBr -promoted intramolecular bromocyclization of N-allylamides and aryl allyl
2
ketone oximes
Chun-Hua Yang, Zhong-Qi Xu, Lili Duan, Yue-Ming Li
PII:
S0040-4020(17)31040-2
10.1016/j.tet.2017.10.025
TET 29028
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 July 2017
Revised Date: 29 September 2017
Accepted Date: 10 October 2017
Please cite this article as: Yang C-H, Xu Z-Q, Duan L, Li Y-M, CuBr -promoted intramolecular
2
bromocyclization of N-allylamides and aryl allyl ketone oximes, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.10.025.
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CuBr2-promoted intramolecular bromocyclization
of N-allylamides and aryl allyl ketone oximes
Leave this area blank for abstract info.
Chun-Hua Yang, Zhong-Qi Xu Lili Duan and Yue-Ming Li
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of
Molecular Drug Research, Nankai University, Tianjin, People’s Republic of China
Ar
R
OH
N
H
CuBr2 (3 equiv)
N
O
N
O
R
N
or
Br
( )n
or
Ar
( )n
CH3CN, 24 h
O
Br
n = 1, 2
n = 1, 2
Up to 95% isolated yields.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
CuBr2-promoted intramolecular bromocyclization of N-allylamides and aryl allyl
ketone oximes
Chun-Hua Yanga,b Zhong-Qi Xua, Lili Duan*,a and Yue-Ming Li*,a
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University,
Tianjin, People’s Republic of China
b College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new and easy-to-perform route to 2-oxazolines amd isoxazolines was reported. Using CuBr2
as both the bromide source and the reaction promoter, bromocyclization of N-allylamides and
allyl ketone oximes proceeded readily, leading to oxazolines and isoxazolines in good to
excellent yields.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Oxazoline
Isoxazoline
CuBr2
Bromocyclization
N-allylamide
1. Introduction
chlorocyclization of unsaturated amides gave the corresponding
oxazolines in high yields.13 In the presence of a suitable chlorine
source, (DHQD)2PHAL-catalyzed asymmetric chlorocyclization
of unsaturated amides furnished chiral oxazolines in high yields
and high ee’s.14 Using NBS as bromine source, chiral phosphine-
catalyzed bromocyclization of allylic amides provided the chiral
oxazolines in high ee’s.15 Iodine,16 NIS,17 I(III),18 or
Oxazoline and isoxazoline moieties1 are important subunits in
natural products2 and synthetic bioactive compounds.3 They are
also frequently found as key structures in important
pharmaceuticals.4 In addition, oxazoline moieties have been
found widespread application as important chiral ligands and
chiral auxiliaries in asymmetric synthesis.5 For these reasons,
significant efforts have been made to develop new and efficient
methods for the formation of oxazolines.6 Traditionally,
oxazolines were prepared from carboxylic acids and β-amino
alcohols under water removal or other dehydrative conditions.7
However, application of such methods was limited due to the
harsh reaction conditions. The breakthrough was made when
Vorbrüggen et al. developed the cyclization of carboxylic acids
with amino alcohols, amino mercaptans or diamines in the
presence of triphenylphosphine, CCl4 and tertiary bases.8 Slow
addition of either triphenylphosphine or CCl4 to the reaction
mixture led to the formation of oxazolines in high yields under
mild conditions.9 Reactions of β-amino alcohols with other
carboxylic acid derivatives such as carboxylic esters,10 nitriles,11
or trimethylorthobenzoate12 also provided the oxazolines in good
yields.
(diacetoxyiodo)benzene19-promoted
iodocyclization
of
unsaturated carboxamides also gave the functionalized
oxazolines in high yields. In the presence of a suitable oxidant,
iodoarene could be in situ oxidized to hypervalent I(III), and
I(III)-catalyzed cyclization of unsaturated amides also provided
oxazolines in high yields.20
It is our purpose to prepare biologically interesting
heterocycles with easily accessible starting materials. Herein, we
wish to report a new method for the preparation of oxazolines
and isoxazolines under mild conditions.
2. Results and discussion
Recently, we have shown that copper(II) could promote
intramolecular bromo- and chloroamination21 of unfunctionalized
olefins
under
mild
conditions,
leading
to
2-
halomethylpyrrolidines or 3-halopiperidines in good to excellent
isolated yields (Scheme 1). Preliminary study of the mechanism
indicated that the reaction generally followed an intramolecular
amination mechanism with the formation of Cu-N intermediate
Recently, electrophile-induced halocyclization of unsaturated
amides also emerged as important methods for the formation of
different 2-oxazolines. Using N-chlorosulfonamide salts such as
chloramine-T as the electrophilic chlorine precursor,
———
* Corresponding author. Tel.: +86-22-23504028; fax: +86-22-2350-7760; e-mail: lduan@nankai.edu.cn, ymli@nankai.edu.cn

2
Tetrahedron
14
2
rt
rt
rt
CHCl3
DCM
DCE
42%
76%
87%
and the subsequent C=C double bond activation upon copper
ACCEPTED MANUSCRIPT
coordination.22
15
16
2
2
R1
R1
R1
R1 R1
Br
R1
CuCl2·2H2O or CuBr2
( )n
NHR2
a The reactions were carried out with 1 mmol of 1a and 50 mL
of solvent.
or
X
( )n
n=1,2
N
N
R2
R2
b Determined by crude 1H NMR analysis.
c NR = no reaction.
R2 = alkyl
R2 = Ts, X = Br
or X = Cl
After the validation of the Cu(II)-promoted reaction,
development of a catalytic version of the reaction was tested.
Based on our understanding of Cu(II) promoted halocyclization
reaction, an oxidant would be applied to regenerate Cu(II) from
Cu(I) formed during the reaction,24,21 and tert-butyl
peroxybenzoate was found to be the most suitable oxidant for the
reaction. Different bromide sources were tested,25 and TMSBr
gave the most promising result (Table 2). In the absence of
CuBr2, only small amount of substrate was converted (Table 2,
entries 1 and 2). This background reaction may be caused by Br2
which was formed via oxidation of Br- in the presence of oxidant.
When 10 mol% of CuBr2 was used, the substrate 1a was
completely converted (Table 2, entry 4). However, considerable
amount of dibrominated product 2a' was also obtained
irrespective of whatever bromine source was used. When NaBr
or KBr was used as the bromide source, only 20% of the
substrate was converted to product 2a (Table 2, entries 6 and 7).
Pyridine hydrobromide salt was also tested as the bromide
source, but increased formation of dibromation product 2a' was
observed (Table 2, entry 8) possibly due to the increase of
background reaction. Similarly, further decreasing the amount of
catalyst also led to the background formation of 2a' (Table 2,
entries 9 and 10). Considering the ease of operation and product
separation of stoichiometric amount of CuBr2-promoted reaction,
development of Cu(II)-catalyzed reaction was not further pursued
at this stage, and the reactions were finally carried out at room
temperature in the presence of 3 equiv of CuBr2.
Scheme 1. Cu(II)-promoted haloamination of
unfunctionalized olefins.
Intramolecular bromoxygenation of N-allyl benzamide 1a was
then trialed to extend the application scope of this Cu(II)-
promoted halocyclization reaction.23 Compound 1a was chosen
based on the assumption that successful intramolecular
bromoxygenation of the substrate would lead to oxazolines that
could be used as important structures in both organic chemistry
and medicinal chemistry. The model reaction was carried out in
acetonitrile with 1 equiv of CuBr2 as both the reaction promoter
and the bromide source. To our delight, 40% of substrate 1a was
converted to the desired 5-bromomethyl-2-phenyl-4,5-
dihydrooxazole 2a after reacting for 24 h at room temperature.
The reaction was then studied in details to get further
information. The reactions were carried out in the presence of
different amount of CuBr2 at different temperatures. The results
are summarized in Table 1.
As shown in Table 1, the reaction did not take place in the
absence of CuBr2 (Table 1, entry 2), and the amount of CuBr2
was very crucial for the reaction. The use 1 equiv of CuBr2 was
not successful, and only 40% of the substrate was converted at
room temperature (Table 1, entry 1). Further increasing the
amount of CuBr2 led to significant increase of the substrate
conversion (Table 1, entries 5-8). However, elevating the
reaction temperature could not significantly increase the
conversion of the substrate (Table 1, entries 3-4). Acetonitrile
was the most suitable solvent among the reaction media tested
(entry 6 vs. entries 9-16), and the reaction proceeded readily at
room temperature in the presence of 3 equiv of CuBr2.
Table 2. CuBr2-catalyzed intramolecular bromoxygenation
reaction of N-allylbenzamide 1a under different conditions a
Ph
O
H
CuBr2
Table 1. CuBr2-promoted intramolecular bromoxygenation
Ph
N
+
N
O
reaction of N-allylbenzamide 1a under different conditions a
Ph
N
H
Br
MeCN, rt
1a
O
Br
Ph
Br
oxidant (1.5 equiv)
H
2a'
2a
CuBr2
Ph
N
conversion b
(2a:2a')
NRc,d
N
O
CuBr2
(equiv)
NO
bromide source
(1.5 equiv)
TMSBr
TMSBr
TMSBr
TMSBr
LiBr
24 h
Entry
1a
O
Br
conversion b
2a
entry
1
CuBr2 (equiv)
temp. (°C)
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
acetone
toluene
THF
1
1
rt
rt
40%
NR c
46%
50%
65%
88%
92%
>95%
NR c
NR c
trace
trace
trace
2
NO
11%
10%d
2
-
3
10%
10%
10%
10%
10%
10%
5%
3
1
40
80
rt
4
>99% (7:1)
87% (4:3)
20%
4
1
5
5
1.5
2
6
NaBr
6
rt
7
KBr
21%
7
2.5
3
rt
8
PyHBr
95% (2:1)
>99% (7:1)
>99% (5:1)
8
rt
9
TMSBr
TMSBr
9
2
rt
10
2.5%
a Reaction conditions: substrate: 1 mmol, reaction time = 12 h,
solvent = CH3CN (50 mL), oxidant = tert-butyl peroxybenzoate
(1.5 equiv).
10
11
12
13
2
rt
2
rt
2
rt
DMF
b Determined by crude 1H NMR analysis.
2
rt
dioxane

3
c NR = no reaction.
d In the absence of oxidant.
Ph
16
86
92
H
ACCEPTED MANUSCRIPT
CuBr2 (3 equiv )
CH3CN
Ph
N
N
O
O
1p
Br
2p
Next, different aryl carboxamides 1b-1q were subjected to the
reaction to extend the scope of the substrates. The results are
summerized in Table 3. As these results showed, 5-bromomethyl-
2-aryloxazolines could be obtained in good to excellent isolated
yields. Electronic effects of the substituents on the aryl groups
showed less impact on the reactions. The substrates with either
electron-donating or electron-withdrawing groups on aromatic
rings could all be cyclized in good isolated yields (2a-2i). The
position of the substituents on the aryl groups also showed less
effect on the reaction (2j-2k). N-Allyl 2-naphthamide 1l could be
converted to the corresponding naphthyloxazoline 2l in high
yield. To our delight, the current method was also suitable for
substituted olefins (2m-2o). When N-(but-3-en-1-yl)benzamide
1p was subjected to the reaction, the dihydro-1,3-oxazine
derivative 2p could be obtained. Reaction of substrate 1q was not
successful, and no intramolecular bromoxygenation product was
detected. In contrast, dibrominated product 2q was isolated in
high yield. De Kimpe et al. reported the synthesis of
functionalized pyrrolidines from N-(benzylidene)- and N-
(Alkylidene)-homoallylamines promoted by electrophiles.26 They
also reported the formation of aziridine rings from N-(arylidene)-
2,3-dibromopropylamines27 and the construction of azitidine
rings from bromine-functionalized aldimines under basic
conditions.28 However, cyclization was not observed under the
current condition.
17
CuBr2 (3 equiv )
CH3CN
H
N
N
O
Br
1q
H
N
Br
N
O
2q
a
Reaction conditions: substrate (1 mmol), Solvent = CH3CN
(50 mL), reaction temperature = room temperature, reaction time
= 24 h.
Reaction of a variety of aliphatic N-allyl carboxamides (3a-
3e) could also be realized, giving the desired 5-bromomethyl-2-
oxazolines (4a-4e) in good isolated yields (Table 4). Increasing
the length of the mainchain of the carboxamides showed less
impact on the reactions (4a-4c). Steric effects of the
carboxamides also showed less impact on the reactions, and
substrates with t-butyl groups could also be cyclized in
satisfactory isolated yields (4d).
Table 4. Cyclization of aliphatic N-allylcarboxamides a
R
H
CuBr2 (3 equiv)
CH3CN
N
O
R
N
O
Br
4a - 4e
3a - 3e
Table 3. Synthesis of 5-bromomethyl-2-oxazolines a
entry
R
product
4a
isolated yield (%)
entry Substrate (R)
product
isolated
yield (%)
1
2
3
4
5
n-C3H7
83
68
88
73
85
Ar
n-C4H9
n-C7H15
t-C4H9
Cy
4b
H
CuBr2 (3 equiv )
CH3CN
Ar
N
N
O
4c
O
1a - 1l
Br
2a - 2l
4d
1
Ph
2a
2b
2c
2d
2e
2f
88
82
95
79
84
82
88
82
89
80
80
86
94
4e
2
4-MeOPh
4-tBuPh
4-NCPh
4-O2NPh
2-FPh
a
Reaction conditions: substrate (1 mmol), solvent = CH3CN
3
(50 mL), reaction temperature = rt, reaction time = 24 h.
4
Cyclization of 1-arylbut-3-en-1-one oximes were also carried
out to further extend the scope of the protocol. Again, several
3,5-disubstituted isoxazolines 6 were obtained in acceptable
isolated yields (Table 5). Electronic property of the substituents
showed some impact on the reaction, and substrate bearing
electron-withdrawing nitro group at para-position of the benzene
ring gave product in only 38% yield (6d).
5
6
7
2-BrPh
2-IPh
2g
2h
2i
8
9
2-MePh
2-ClPh
4-ClPh
Table 5. Synthesis of 5-bromomethyl-3-isoxazolines a
10
11
12
13
2j
Ar
OH
2k
2l
CuBr2 (3 equiv)
CH3CN
N
N
2-Naphthyl
O
Ar
Br
Ar
5a - 5d
H
6a - 6d
CuBr2 (3 equiv )
CH3CN
Ar
N
N
O
entry
Ar
product
6a
isolated yield (%)
1m
O
O
Br
2m
1
2
3
4
Ph
63
81
55
38
Ph
14
15
76
75
H
N
4-MeOPh
4-BrPh
4-O2NPh
6b
CuBr2 (3 equiv )
Ph
Ph
N
O
CH3CN
6c
1n
1o
Br
2n
6d
Ph
Ph
a
H
N
Reaction conditions: substrate (1 mmol), Solvent = CH3CN
(50 mL), reaction temperature = room temperature, reaction time
= 24 h.
CuBr2 (3 equiv )
CH3CN
Ph
N
O
O
Br
2o
To demonstrate the scalability of the protocol, a gram-scale
synthesis of 2c was also carried out. Cyclization of N-

4
Tetrahedron
ACCEPTED MANUSCRIPT
allylbenzamides 1c on 10.0 mmol scale afforded the desired
proceeded readily without the use of argon or nitrogen protection.
2,5-disubstituted oxazoline 2c in 88% isolated yield (Scheme 2).
The obtained cyclized products could be further functionalized
via different nucleophilic substitution reactions. The
intramolecular bromoxygenation reactions were easy to carry out.
The good isolated yields, mild reaction conditions, and the easy-
to-operate feature made the current reaction an attractive method
for the synthesis of a variety of 2,5-disubstituted oxazolines.
Br
O
N
CuBr2 (3 equiv)
CH3CN, rt, 24 h
O
N
H
1c 10 mmol, 2.71 g
2c 2.6 g, 88% yield
4. Experimental Section
Scheme 2. Gram-scale synthesis of oxazoline 2c.
4.1 General experimental information
The 5-bromomethyl-2-oxazoline can be employed for the
synthesis of various 2,5-disubstituted oxazolines by conventional
nucleophilic substitution reactions (Scheme 3). For example,
bromine atom in 2c could be replaced by different nucleophiles
such as acetate (7a) or azide (7b) under mild conditions.
Reactions were carried out with commercially available
reagents in oven-dried apparatus, and the use of argon or nitrogen
atmosphere was generally not required.. 1H and 13C NMR spectra
were recorded at 298 K using deuterated chloroform as solvent
and TMS as internal reference. Column chromatography was
performed employing 200-300 mesh silica gel unless otherwise
noted. Thin layer chromatography (TLC) was performed on silica
gel GF254. Melting points were measured on a digital melting-
point apparatus without correction of the thermometer. HRMS
analyses were carried out with Varian FTICR-MS 7.0T. Infrared
(IR) spectra were recorded with KBr pellet, and wavenumbers
were given in cm-1. Unless otherwise indicated, starting
materials and reagents used in the study were purchased and were
used as received without further purification. Substrates were
prepared according to our previous works.25a
Br
OAc
N
N
NaOAc, DMF
100°C, 4h
O
O
7a 89% yield
2c
Br
N3
N
N
O
NaN3, DMF
90°C, 2h
O
2c
7b 93% yield
Scheme 3. Derivatization of oxazoline 2c.
4.2 General procedure for the synthesis 5-bromomethyl-2-
oxazolines
In our previous study on Cu(II)-promoted haloamination
reactions, we found that Cu(I) was formed during the
reaction.21,24 In the current reaction system, no product was
detected at all (Table 2, entry 1) when the reaction was carried
out in the absence of both CuBr2 and oxidant, indicating a crucial
role played by the promotor. When catalytic amount of promotor
was used, only small amount of substrate was converted to the
product when an oxidant was not present in the reaction system
(Table 2, entry 3), and complete substrate conversion was
observed when the reaction was carried out in the presence of
catalytic amount of CuBr2 along with suitable amount of bromide
source and an appropriate oxidant. These results were in good
agreement with our previous finding in Cu(II)-promoted
haloamination reactions.21,24 On the basis of these results and our
understanding of Cu(II)-promoted halo-cyclization reactions, a
preliminary reaction pathway was proposed as shown in Scheme
4. The C=C double bond in the substrate was first activated upon
copper coordination (A). Intramolecular nucleophilic attack of
oxygen atom on this activated C=C double bond produced an
aminocupration intermediate B and cleavage of the C-Cu bond22b
gave C as the final product
In a 100 mL round bottom flask were added N-allyl
carboxamides (1 mmol), CH3CN (50 mL) and CuBr2 (3 mmol).
The reaction mixture was stirred at room temperature for 24 h.
CH2Cl2 (50 mL) was then added and the mixture was washed
with aqueous EDTA. The organic layer was dried (MgSO4) and
concentrated to give the crude residue. The residue was purified
with silica gel column to give the corresponding product.
4.2.1. 5-(Bromomethyl)-2-phenyl-4,5-dihydrooxazole (2a)
Compound 2a was prepared according to the general
procedure and was isolated as colorless oil (210 mg, 88% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
NMR (400 MHz, CDCl3) δ 7.95-7.93 (m, 2H), 7.51-7.47 (m,
1H), 7.42 (t, J = 7.4 Hz, 2H), 4.97-4.90 (m, 1H), 4.19 (dd, J =
15.2, 9.6 Hz, 1H), 3.92 (dd, J = 15.2, 6.6 Hz, 1H), 3.58-3.48 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 163.7, 131.7, 128.5, 128.3,
127.4, 78.0, 59.5, 33.8. Spectral data were consistent with 5-
bromomethyl-2-phenyl-4,5-dihydrooxazole.29
1
4.2.2. 5-(Bromomethyl)-2-(4-methoxyphenyl)-4,5-
dihydrooxazole (2b)
H
H
N
Ar
N
Ar
CuBr2
-HBr
Compound 2b was prepared according to the general
procedure and was isolated as white solid (220 mg, 82% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp
O
O
Cu
Br
A
1
Br
= 91-92 °C. H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.7 Hz,
N
Ar
N
Ar
2H), 6.88 (d, J = 8.7 Hz, 2H), 4.91-4.84 (m, 1H), 4.12 (dd, J =
14.8, 9.6 Hz, 1H), 3.84 (dd, J = 14.9, 6.6 Hz, 1H), 3.79 (s, 3H),
3.52-3.44 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 163.5, 162.3,
130.0, 119.5, 113.8, 77.9, 59.0, 55.4, 33.8. Spectral data were
consistent with reported 5-bromomethyl-2-(4-methoxyphenyl)-
4,5-dihydrooxazole.30
Br
Cu
O
O
B
Br
C
CuBr2 2 CuBr
Scheme 4. A preliminary mechanism for CuBr2-promoted
intramolecular bromocyclization of N-allylamides.
3. Conclusion
4.2.3. 5-(Bromomethyl)-2-(4-tert-butylphenyl)-4,5-
dihydrooxazole (2c)
In summary, we have reported a practical copper (II)-
promoted intramolecular bromoxygenation of N-allyl amides and
oximes. Using 3 equiv of CuBr2 as both the reaction promoter
and the bromide source, direct intramolecular bromoxygenation
Compound 2c was prepared according to the general
procedure and was isolated as white solid (280 mg, 95% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp

5
1
= 69-72 °C. H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz,
Compound 2h was prepared according to the general
ACCEPTED MANUSCRIPT
2H), 7.39 (d, J = 8.2 Hz, 2H), 4.87-4.80 (m, 1H), 4.10 (dd, J =
15.0, 9.6 Hz, 1H), 3.84 (dd, J = 15.0, 6.5 Hz, 1H), 3.48-3.40 (m,
2H), 1.28 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 163.4, 154.8,
127.9, 125.2, 124.4, 77.6, 59.1, 34.8, 33.7, 31.0. IR: 2952, 2867,
1718, 1652, 1366, 849 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C14H18BrNO, 296.0650; found: 296.0649.
procedure and was isolated as yellow oil (300 mg, 82% yield)
after flash chromatography (EtOAc/petroleum ether 1:9 v/v). H
1
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 7.58 (d, J =
7.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H),
4.95-4.83 (m, 1H), 4.14 (dd, J = 14.7, 10.1 Hz, 1H), 3.88 (dd, J =
15.1, 6.4 Hz, 1H), 3.59-3.42 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 163.5, 140.4, 132.7, 131.7, 130.7, 127.7, 78.0, 59.3,
33.6. IR: 2924, 1729, 1633, 1586, 1252, 744 cm-1. HRMS–ESI
(m/z): [M+H]+ calcd for C10H9BrINO, 365.8990; found:
365.8979.
4.2.4. 4-(5-Bromomethyl-4,5-dihydrooxazol-2-yl)benzonitrile
(2d)
Compound 2d was prepared according to the general
procedure and was isolated as white solid (210 mg, 79% yield)
after flash chromatography (EtOAc/petroleum ether 1:6 v/v), mp
4.2.9. 5-Bromomethyl-2-(o-tolyl)-4,5-dihydrooxazole (2i)
1
= 98-100 °C. H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz,
Compound 2i was prepared according to the general
2H), 7.62 (d, J = 8.0 Hz, 2H), 4.96-4.89 (m, 1H), 4.14 (dd, J =
15.5, 9.8 Hz, 1H), 3.87 (dd, J = 15.5, 6.7 Hz, 1H), 3.50-3.48 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 161.9, 132.1, 131.3, 128.7,
118.1, 114.7, 78.2, 59.4, 33.7. IR: 2932, 2872, 2231, 1726, 1652,
1506, 1069, 850 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C11H9BrN2O, 264.9977; found: 264.9971.
procedure and was isolated as colorless oil (225 mg, 89% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
1
NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.39 (t, J =
7.3 Hz, 1H), 7.30-7.26 (m, 2H), 4.94-4.87 (m, 1H), 4.23 (dd, J =
15.0, 9.8 Hz, 1H), 3.97 (dd, J = 15.1, 6.5 Hz, 1H), 3.57-3.56 (m,
2H), 2.65 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.7, 138.6,
131.1, 130.6, 129.7, 126.6, 125.4, 76.8, 59.4, 34.0, 21.7. IR:
3000, 1725, 1627, 1575, 1248, 740 cm-1. HRMS–ESI (m/z):
[M+H]+ calcd for C11H12BrNO, 254.0181; found: 254.0177.
4.2.5. 5-Bromomethyl-2-(4-nitrophenyl)-4,5-dihydrooxazole
(2e)
4.2.10. 5-Bromomethyl-2-(2-chlorophenyl)-4,5-
dihydrooxazole (2j)
Compound 2e was prepared according to the general
procedure and was isolated as yellow solid (240 mg, 84% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), m
Compound 2j was prepared according to the general
procedure and was isolated as yellow oil (220 mg, 80% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
1
p= 119-121 °C. H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8
1
Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 4.97-4.90 (m, 1H), 4.16 (dd, J
= 15.6, 9.8 Hz, 1H), 3.89 (dd, J = 15.6, 6.8 Hz, 1H), 3.50 (d, J =
5.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 161.8, 149.5, 133.1,
129.2, 123.6, 78.4, 59.5, 33.7. IR: 2953, 2926, 2865, 1726, 1648,
1599, 1520, 1337, 859 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C10H9BrN2O3, 284.9875; found: 284.9868.
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 1H), 7.35 (d, J =
7.9 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H),
4.86-4.81 (m, 1H), 4.13 (dd, J = 15.1, 9.8 Hz, 1H), 3.87 (dd, J =
15.2, 6.4 Hz, 1H), 3.46-3.42 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 161.9, 133.3, 131.7, 131.2, 130.7, 126.8, 126.5, 77.6,
59.4, 33.6. IR: 2872, 1733, 1636, 1597, 753 cm-1. HRMS–ESI
(m/z): [M+H]+ calcd for C10H9BrClNO, 273.9634; found:
273.9630.
4.2.6. 5-Bromomethyl-2-(2-fluorophenyl)-4,5-dihydrooxazole
(2f)
4.2.11. 5-Bromomethyl-2-(4-chlorophenyl)-4,5-
dihydrooxazole (2k)
Compound 2f was prepared according to the general
procedure and was isolated as yellow oil (210 mg, 82% yield)
1
after flash chromatography (EtOAc/petroleum ether 1:9 v/v). H
Compound 2k was prepared according to the general
procedure and was isolated as white solid (220 mg, 80% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp
NMR (400 MHz, CDCl3) δ 7.79 (t, J = 7.4 Hz, 1H), 7.39-7.35
(m, 1H), 7.13-7.04 (m, 2H), 4.87-4.80 (m, 1H), 4.14 (dd, J =
15.2, 9.8 Hz, 1H), 3.88 (dd, J = 15.3, 6.6 Hz, 1H), 3.47-3.41 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 161.1 (d, J = 258.5 Hz),
160.0 (d, J = 5.8 Hz), 133.0 (d, J = 8.7 Hz), 130.8, 123.9 (d, J =
3.8 Hz), 116.7 (d, J = 21.8 Hz), 115.5 (d, J = 10.3 Hz), 77.1,
59.5, 33.6. 19F NMR (376 MHz, CDCl3): -109.3. IR: 2937, 1727,
1634, 1583, 1256, 763 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C10H9BrFNO, 257.9930; found: 257.9929.
1
= 64-67 °C. H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz,
2H), 7.28 (d, J = 8.4 Hz, 2H), 4.86-4.79 (m, 1H), 4.07 (dd, J =
15.2, 9.7 Hz, 1H), 3.79 (dd, J = 15.2, 6.7 Hz, 1H), 3.46-3.39 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 162.6, 137.6, 129.5, 128.6,
125.7, 78.0, 59.3, 33.7. IR: 2944, 2874, 1722, 1645, 1596, 1487,
1264, 845 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C10H9BrClNO, 273.9634; found: 273.9629.
4.2.7. 5-Bromomethyl-2-(2-bromophenyl)-4,5-dihydrooxazole
(2g)
4.2.12. 5-Bromomethyl-2-(naphthalen-2-yl)-4,5-
dihydrooxazole (2l)
Compound 2g was prepared according to the general
Compound 2l was prepared according to the general
procedure and was isolated as yellow solid (250 mg, 86% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp
procedure and was isolated as yellow oil (280 mg, 88% yield)
1
after flash chromatography (EtOAc/petroleum ether 1:6 v/v). H
NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 1H), 7.55 (d, J =
7.8 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.22-7.18 (m, 1H), 4.88-
4.83 (m, 1H), 4.12 (dd, J = 14.9, 9.9 Hz, 1H), 3.86 (dd, J = 15.1,
6.3 Hz, 1H), 3.51-3.43 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
162.7, 133.9, 131.9, 131.4, 129.1, 127.2, 121.8, 78.0, 59.5, 33.6.
IR: 2871, 1732, 1633, 1248, 749 cm-1. HRMS–ESI (m/z):
[M+H]+ calcd for C10H9Br2NO, 317.9129; found: 317.9123.
1
= 114-116 °C. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.91
(d, J = 8.4 Hz, 1H), 7.80-7.69 (m, 3H), 7.45-7.33 (m, 2H), 4.85-
4.79 (m, 1H), 4.09 (dd, J = 14.9, 9.7 Hz, 1H), 3.82 (dd, J = 15.0,
6.6 Hz, 1H), 3.46-3.38 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
163.8, 134.8, 132.6, 128.9, 128.8, 128.2, 127.8, 127.7, 126.6,
124.7, 124.6, 78.0, 59.4, 33.8. IR: 2928, 1729, 2655, 1525, 1244,
820 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for C14H12BrNO,
290.0181; found: 290.0180.
4.2.8. 5-Bromomethyl-2-(2-iodophenyl)-4,5-dihydrooxazole
(2h)

6
Tetrahedron
ACCEPTED MANUSCRIPT
1
4.2.13. 5-bromomethyl-5-methyl-2-phenyl-4,5-
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
dihydrooxazole (2m)
NMR (400 MHz, CDCl3) δ 4.65-4.59 (m, 1H), 3.87-3.80 (m,
1H), 3.58-3.53 (m, 1H), 3.34-3.33 (m, 2H), 2.15-2.13 (m, 2H),
1.60-1.51 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 167.4, 77.2, 58.6, 33.9, 29.8, 29.6, 19.2, 13.6. IR: 2964,
2879, 1743, 1593 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C7H12BrNO, 206.0181; found: 206.0172.
Compound 2m was prepared according to the general
procedure and was isolated as yellow oil (240 mg, 94% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
1
NMR (400 MHz, CDCl3) δ 7.93-7.91 (m, 2H), 7.47-7.37 (m,
3H), 4.06 (d, J = 15.0 Hz, 1H), 3.79 (d, J = 15.0 Hz, 1H), 3.52 (q,
J = 10.6 Hz, 2H), 1.60 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
163.0, 131.4, 128.4, 128.2, 127.7, 84.1, 64.7, 38.9, 24.5. IR:
2902, 1721, 1633, 1278, 716 cm-1. HRMS–ESI (m/z): [M+H]+
calcd for C11H12BrNO, 254.0181; found: 254.0175.
4.2.19. 5-Bromomethyl-2-butyl-4,5-dihydrooxazole (4b)
Compound 4b was prepared according to the general
procedure and was isolated as colorless oil (150 mg, 68% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
1
4.2.14. 5-(1-Bromo-1-phenylmethyl)-2-phenyl-4,5-
dihydrooxazole (2n)
NMR (400 MHz, CDCl3) δ 4.66-4.59 (m, 1H), 3.84 (dd, J = 14.5,
9.7 Hz, 1H), 3.57 (dd, J = 14.5, 6.5 Hz, 1H), 3.37-3.30 (m, 2H),
2.18 (t, J = 7.6 Hz, 2H), 1.54-1.50 (m, 2H), 1.31-1.26 (m, 2H),
0.83 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.6,
77.2, 58.7, 33.9, 27.9, 27.6, 22.2, 13.6. IR: 2957, 2868, 1708,
1650, 1264, 712 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C8H14BrNO, 220.0337; found: 220.0323.
Compound 2n was prepared according to the general
procedure and was isolated as yellow solid (240 mg, 76% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp
1
= 92-94 °C. H NMR (400 MHz, CDCl3) δ 7.99-7.94 (m, 2H),
7.50-7.35 (m, 8H), 5.34 (d, J = 8.1 Hz, 1H), 4.32 (td, J = 8.3, 4.9
Hz, 1H), 4.08 (dd, J = 17.1, 4.9 Hz, 1H), 3.94 (dd, J = 17.2, 8.3
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 155.3, 137.6, 132.7,
131.0, 129.1, 128.7, 128.2, 127.3, 127.0, 80.8, 50.7, 45.6. IR:
2910, 2852, 1770, 1657, 1580, 1338, 1179, 696 cm-1. HRMS–ESI
(m/z): [M+H]+ calcd for C16H14BrNO, 316.0337; found:
316.0335.
4.2.20. 5-Bromomethyl-2-heptyl-4,5-dihydrooxazole (4c)
Compound 4c was prepared according to the general
procedure and was isolated as colorless oil (230 mg, 88% yield)
1
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
NMR (400 MHz, CDCl3) δ 4.68-4.61 (m, 1H), 3.87 (dd, J = 14.4,
9.8 Hz, 1H), 3.59 (dd, J = 14.5, 6.5 Hz, 1H), 3.37-3.35 (m, 2H),
2.19 (t, J = 7.6 Hz, 2H), 1.58-1.54 (m, 2H), 1.25-1.19 (m, 8H),
0.81 (t, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.6,
77.2, 58.6, 33.8, 31.5, 29.0, 28.7, 27.8, 25.7, 22.4, 13.9. IR: 2928,
2860, 1740, 1638, 1163 cm-1. HRMS–ESI (m/z): [M+H]+ calcd
for C11H20BrNO, 262.0807; found: 262.0796.
4.2.15. 5-(2-bromopropan-2-yl)-2-phenyl-4,5-dihydrooxazole
(2o)
Compound 2o was prepared according to the general
procedure and was isolated as yellow solid (200 mg, 75% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp
1
= 60-63 °C. H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.1 Hz,
4.2.21. 5-Bromomethyl-2-(tert-butyl)-4,5-dihydrooxazole (4d)
2H), 7.50-7.30 (m, 3H), 4.17-4.15 (m, 1H), 4.01 (dd, J = 17.5,
2.7 Hz, 1H), 3.85 (dd, J = 17.4, 9.5 Hz, 1H), 1.57 (s, 3H), 1.49 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 155.0, 133.4, 130.8, 128.2,
127.2, 77.4, 51.0, 50.1, 27.4, 22.2. IR: 1980, 2934, 1714, 1653,
1256, 693 cm-1. HRMS–ESI (m/z): [M+H]+ calcd for
C12H14BrNO, 268.0337; found: 268.0333.
Compound 4d was prepared according to the general
procedure and was isolated as yellow oil (160 mg, 73% yield)
1
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
NMR (400 MHz, CDCl3) δ 4.61-4.59 (m, 1H), 3.80 (dd, 1H),
3.55 (dd, J = 14.4, 6.0 Hz, 1H), 3.31-3.30 (m, 2H), 1.09 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 173.7, 77.1, 58.5, 34.0, 33.2,
27.5. IR: 2967, 2875, 1732, 1641, 1536, 1149 cm-1. HRMS–ESI
(m/z): [M+H]+ calcd for C8H14BrNO, 220.0337; found: 220.0331.
4.2.16. 6-Bromomethyl-2-phenyl-5,6-dihydro-4H-1,3-oxazine
(2p)
Compound 2p was prepared according to the general
4.2.22. 5-Bromomethyl-2-cyclohexyl-4,5-dihydrooxazole (4e)
procedure and was isolated as oil (218 mg, 86% yield) after flash
chromatography (EtOAc/petroleum ether 1:6 v/v). H NMR (400
Compound 4e was prepared according to the general
1
procedure and was isolated as yellow oil (210 mg, 85% yield)
MHz, CDCl3) δ 7.94-7.92 (m, 2H), 7.45-7.36 (m, 3H), 4.47-4.43
(m, 1H), 3.75-3.52 (m, 4H), 2.15-2.10 (m, 1H), 1.87-1.80 (m,
1H). 13C NMR (100 MHz, CDCl3) δ 155.4, 133.5, 130.8, 128.2,
127.2, 73.8, 42.5, 34.0, 25.8. Spectral data was consistent with 6-
(Bromomethyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazine.31
1
after flash chromatography (EtOAc/petroleum ether 1:4 v/v). H
NMR (400 MHz, CDCl3) δ 4.63-4.56 (m, 1H), 3.81 (dd, J = 13.8,
10.3 Hz, 1H), 3.54 (dd, J = 14.4, 6.3 Hz, 1H), 3.32-3.31 (m, 2H),
2.17 (t, J = 11.1 Hz, 1H), 1.86-1.75 (m, 2H), 1.66-1.64 (m, 2H),
1.55-1.53 (m, 1H), 1.33-1.26 (m, 2H), 1.21-1.04 (m, 3H). 13C
NMR (100 MHz, CDCl3) δ 170.6, 76.8, 58.4, 37.2, 34.1, 29.6,
29.5, 25.7, 25.4, 25.4. IR: 2936, 2858, 1741, 1452, 711 cm-1.
HRMS–ESI (m/z): [M+H]+ calcd for C10H16BrNO, 246.0494;
found: 246.0484.
4.2.17. N-(2,3-dibromopropyl)picolinamide (2q)
Compound 2q was prepared according to the general
procedure and was isolated as white solid (295 mg, 92% yield)
after flash chromatography (EtOAc/petroleum ether 1:4 v/v), mp
1
= 94-96 °C. H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 4.4 Hz,
4.2.23. 5-Bromomethyl-3-phenyl-4,5-dihydroisoxazole (6a)
1H), 8.41 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.75 (td, J = 7.7, 1.7
Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 4.40-4.37 (m, 1H),
4.09-4.00 (m, 1H), 3.84-3.73 (m, 2H), 3.67-3.62 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 164.5, 149.1, 148.1, 137.3, 126.4,
122.2, 50.9, 44.0, 33.7. HRMS–ESI (m/z): [M+H]+ calcd for
C9H10Br2N2O, 320.9238; found: 320.9232.
Compound 6a was prepared according to the general
procedure and was isolated as white solid (150 mg, 63% yield)
after flash chromatography (EtOAc/petroleum ether 1:6 v/v), mp
1
= 59-61 °C. H NMR (400 MHz, CDCl3) δ 7.68-7.67 (m, 2H),
7.50-7.30 (m, 3H), 5.08-4.92 (m, 1H), 3.59-3.55 (m, 1H), 3.51-
3.47 (m, 1H), 3.41 (t, J = 9.0 Hz, 1H), 3.35-3.29 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 156.1, 130.5, 129.1, 128.9, 126.9,
79.8, 39.7, 33.3. Spectral data was consistent with 5-
(bromomethyl)-3-phenyl-4,5-dihydroisoxazole.32
4.2.18. 5-Bromomethyl-2-propyl-4,5-dihydrooxazole (4a)
Compound 4a was prepared according to the general
procedure and was isolated as yellow oil (170 mg, 83% yield)

7
4.2.24. 5-Bromomethyl-3-(4-methoxyphenyl)-4,5-
dihydroisoxazole (6b)
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz,
ACCEPTED MANUSCRIPT
2H), 7.44 (d, J = 8.2 Hz, 2H), 4.91-4.85 (m, 1H), 4.14 (dd, J =
14.8, 9.8 Hz, 1H), 3.80 (dd, J = 14.9, 6.8 Hz, 1H), 3.48-3.40 (m,
2H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 163.9, 155.2,
128.2, 125.5, 124.5, 78.2, 57.9, 54.2, 35.1, 31.3. HRMS–ESI
(m/z): [M+H]+ calcd for C14H18N4O, 259.1559; found: 259.1552.
Compound 6b was prepared according to the general
procedure and was isolated as white solid (220 mg, 81% yield)
after flash chromatography (EtOAc/petroleum ether 1:6 v/v), mp
1
= 73-75 °C. H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.5 Hz,
2H), 6.90 (d, J = 8.5 Hz, 2H), 4.97-4.90 (m, 1H), 3.81 (s, 3H),
3.56-3.52 (m, 1H), 3.49-3.36 (m, 2H), 3.29-3.23 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 161.2, 155.6, 128.3, 121.5, 114.2,
79.4, 55.4, 39.8, 33.4. Spectral data was consistent with 5-
bromomethyl-3-(4-methoxyphenyl)-4,5-dihydroisoxazole.33
5. Appendix A. Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2017.XX.XXX.
Acknowledgments
4.2.25. 5-Bromomethyl-3-(4-bromophenyl)-4,5-
dihydroisoxazole (6c)
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 21672106, NSFC
21272121). YMLi acknowledges the support from “The
Fundamental Research Funds for the Central Universities
(63171337)”.
Compound 6c was prepared according to the general
procedure and was isolated as off-white solid (175 mg, 55%
yield) after flash chromatography (EtOAc/petroleum ether 1:9
1
v/v), mp = 115-117 °C. H NMR (400 MHz, CDCl3) δ 7.53-7.48
(m, 4H), 5.03-4.96 (m, 1H), 3.58-3.54 (m, 1H), 3.50-3.39 (m,
2H), 3.30-3.24 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 155.4,
132.1, 128.3, 127.9, 124.8, 80.0, 39.4, 33.3. Spectral data was
References and notes
consistent
with
5-bromomethyl-3-(4-bromophenyl)-4,5-
dihydroisoxazole.32
1. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
2. (a) Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey, E.
J.; Parry, D. L.; Watters, D. J. J. Med. Chem. 1989, 32, 1354; (b)
Bode, H. B.; Irschik, H.; Wenzel, S. C.; Reichenbach, H.;
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M.; Yamakawa, M.; Oka, S.; Tanaka, Y.; Hoshino, Y.; Mikami,
Y.; Sato, A.; Fujiwara, H.; Ohizumi, Y.; Kobayashi, J. i. J. Nat.
Prod. 2005, 68, 462.
3. (a) Li, X.; McCoy, K. A.; Murray, W. V.; Jolliffe, L.; Pulito, V.
Bioorg. Med. Chem. Lett. 2000, 10, 2375; (b) Alam, A.; Pal, C.;
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Bindu, S.; Sarkar, S.; Pal, U.; Maiti, N. C.; Adhikari, S.;
Bandyopadhyay, U. Bioorg. Med. Chem. 2011, 19, 7365.
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Barr, K. J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hui, Y. H.; Lee, J.;
Warner, R. B.; Kovar, P.; Nukkala, M. A.; Zielinski, N. A.;
Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.;
Ng, S.-C.; Rosenberg, S.; Sham, H. L. Bioorg. Med. Chem. Lett.
2002, 12, 465; (b) Barbachyn, M. R.; Cleek, G. J.; Dolak, L. A.;
Garmon, S. A.; Morris, J.; Seest, E. P.; Thomas, R. C.; Toops, D.
S.; Watt, W.; Wishka, D. G.; Ford, C. W.; Zurenko, G. E.;
Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H.; Adams,
W. J.; Friis, J. M.; Slatter, J. G.; Sams, J. P.; Oien, N. L.; Zaya,
M. J.; Wienkers, L. C.; Wynalda, M. A. J. Med. Chem. 2003, 46,
284; (c) Pulkkinen, J. T.; Honkakoski, P.; Peräkylä, M.; Berczi,
I.; Laatikainen, R. J. Med. Chem. 2008, 51, 3562.
4.2.26. 5-Bromomethyl-3-(4-nitrophenyl)-4,5-
dihydroisoxazole (6d)
Compound 6d was prepared according to the general
procedure and was isolated as yellow solid (108 mg, 38% yield)
after flash chromatography (EtOAc/petroleum ether 1:6 v/v), mp
= 159-161 °C. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 6.8 Hz,
2H), 7.85 (d, J = 6.8 Hz, 2H), 5.14-5.07 (m, 1H), 3.63-3.33 (m,
4H). 13C NMR (100 MHz, CDCl3) δ 154.7, 148.8, 135.2, 127.7,
124.2, 80.8, 39.2, 33.0. Spectral data was consistent with 5-
(bromomethyl)-3-(4-nitrophenyl)-4,5-dihydroisoxazole.34
4.3. Esterification of 5-bomomethyl-2-oxazoline 2c
In a 50 mL round bottom flask were added 5-bomomethyl-2-
oxazoline 2c (1 mmol), NaOAc (164 mg, 2 mmol), and DMF (25
mL). The reaction mixture was heated to 100 °C and was stirred
at this temperature for 4 h. After the reaction mixture was cooled
to room temperature, CH2Cl2 (50 mL) was added and the reaction
mixture was washed with water. The organic layer was dried
(MgSO4) and concentrated to give crude residue which was
purified by silica gel column chromatography with
EtOAc/petroleum ether 3:1, v/v) as an eluent to give 2-{[4-(tert-
butyl)phenyl]-4,5-dihydrooxazol-5-yl}methyl acetate (7a, 245
1
mg, 89% yield) as colorless oil. H NMR (400 MHz, CDCl3) δ
7.85 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 4.88-4.87 (m,
1H), 4.28 (dd, J = 12.0, 2.5 Hz, 1H), 4.19-4.09 (m, 2H), 3.79 (dd,
J = 14.8, 7.2 Hz, 1H), 2.07 (s, 3H), 1.31 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 170.9, 164.0, 155.0, 128.1, 125.4, 124.7, 76.8,
65.3, 57.0, 35.0, 31.2, 20.9. HRMS–ESI (m/z): [M+H]+ calcd for
C16H21NO3, 276.1600; found: 276.1611.
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4.4. Azidation of 5-bomomethyl-2-oxazoline 2c
In a 50 mL round bottom flask were added 5-bomomethyl-2-
oxazoline 2c (1 mmol), NaN3 (130 mg, 2 mmol), and DMF (25
mL). The reaction mixture was heated to 90 °C and was stirred at
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